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JosÃ© Baselga, MD, PhD, explores the dual inhibition of cell-signaling pathways in breast cancer on several fronts, including new therapies for patients with the HER2-positive subtype and novel ways to target mTOR and the PI3K/Akt/mTOR pathway.
José Baselga, MD, PhD
José Baselga, MD, PhD, has explored the dual inhibition of cell-signaling pathways in breast cancer on several fronts, including new therapies for patients with the HER2-positive subtype and novel ways to target mTOR and the PI3K/Akt/mTOR pathway.
The translational researcher shared his expertise on those topics in three presentations during the 30th Annual Miami Breast Cancer Conference (MBCC), March 7-10, in Miami Beach, Florida. The conference was hosted by Physicians’ Education Resources (PER).
He offered OncologyLive the abstracts of his MBCC talks in response to questions about his research. The following are excerpts from those abstracts.
Since you’ve been so involved in developing treatments for HER2- positive breast cancer, let’s start with your talk on “Advanced HER2-Positive Breast Cancer: New Options and How to Deploy Them.” Please give us some insights about what you addressed.
The therapy of patients with advanced HER2- positive breast cancer is rapidly changing on several fronts. There seems to be a decrease in the number of patients with advanced disease due to the introduction of trastuzumab-containing adjuvant therapy. In addition, there is an increasing understanding of the biology of HER2 disease, and we are witnessing the emergence of novel and more potent therapeutic anti-HER2 agents such as HER2 small-molecule tyrosine kinase inhibitors, anti-HER2 antibodydrug conjugates, inhibitors of HER2 dimerization, and rapamycin analogues.
Currently, available studies support the superiority of first-line therapy with a combination of taxanes, trastuzumab, and the HER2 dimerization inhibitor pertuzumab. Similarly, in the second-line setting, the anti-HER2 antibody-drug conjugate T-DM1 has shown superiority over capecitabine in combination with lapatinib. In addition, a dual blockade with trastuzumab and lapatinib has confirmed superiority over single-agent anti-HER2 therapy.
New areas of research include the identification of a population of patients with HER2-positive breast cancer that may not require the administration of chemotherapy; the selection of the type of anti-HER2 therapy based on the global mutational status of the tumor; and the potential role of mTOR inhibitors and PI3K inhibitors as combination partners to anti-HER2 therapy.
You focused on mTOR inhibitors in another of your talks, titled “mTOR Inhibitors: Reversing Resistance to Endocrine Blockade Therapy.” Why have mTOR inhibitors become so important in the treatment of hormone receptorpositive breast cancer?
Hormonal therapy represents the mainstay of treatment of patients with metastatic hormone receptor (HR)-positive breast cancer. However, resistance to hormonal therapy, either de novo or acquired, is currently a major limitation in the therapy of this disease, and new therapeutic strategies are needed to enhance the efficacy of currently available treatment regimens.
The study of resistance to endocrine therapies in HR-positive breast cancer has aimed at identifying new therapeutic strategies that would enhance the efficacy of endocrine therapies. An emerging mechanism of endocrine resistance is aberrant signaling via the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway.
Recently, we conducted a phase III study comparing the mTOR inhibitor everolimus and exemestane to exemestane and placebo in 724 patients with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors [N Engl J Med. 2012; 366(6):520-529]. In this pivotal study, the combination of everolimus and exemestane resulted in marked improvement in progression-free survival as determined by local investigator assessment (6.9 vs 2.8 months; hazard ratio [HR] 0.43, P = 1.4×10-15) and by central assessment (10.6 vs 4.1 months; HR 0.36, P = 3.3×10-15). The clinical benefit observed in the combination arm also far exceeds the clinical benefit of single-agent everolimus in a similar population of patients.
The striking clinical benefit observed with the combination of an mTOR inhibitor, an agent marginally active in this clinical setting, and an aromatase inhibitor in a hormone-refractory patient population suggests a true synergism that requires careful analysis. In preclinical models, activation of PI3K/ mTOR is required for the adaptation of estrogen receptor (ER)-positive cells to hormone deprivation, and combined estrogen deprivation and PI3K/Akt/ mTOR pathway inhibition causes synthetic lethality in ER-positive breast cancer cells.
We are currently molecularly characterizing these compensatory pathways. In addition, we are studying whether the estrogen degrader fulvestrant may be superior to the aromatase inhibitor exemestane. Since both ligand-dependent and ligand-independent ER signaling can be inhibited with fulvestrant, it is tempting to speculate that this agent will be more efficacious than exemestane when combined with everolimus.
The end result of our proposal would be the selection of novel strategies to block mTOR-mediated compensatory pathways and, importantly, to identify the patient population more likely to respond to combined ER/mTOR blockade.
Another way to block signaling from the PI3K/Akt/mTOR pathway is to inhibit the expression of PI3K, and this was the subject of your talk titled “Update on the New PI3K Inhibitors in Breast Cancer.” What’s on the horizon in the area of PI3K inhibition?
Pharmacologic and genetic evidence points to the PI3K/Akt/mTOR pathway as a key mediator of oncogenic signaling in several breast cancer subtypes. Activation of this pathway has been demonstrated to be necessary for tumor maintenance in cancers harboring amplification of the HER2 receptor tyrosine kinase (RTK), loss of the PTEN or INPP4B tumor suppressors, or mutational activation of the lipid kinase PI3K. Despite the biological heterogeneity of breast cancers, these alterations are highly prevalent, and at least one of these alterations may be found in as many as 70% of all breast tumors.
Direct pharmacologic inhibition of PI3K/Akt/ mTOR signaling is, therefore, an attractive clinical strategy for breast cancer. In addition to mTOR inhibitors already approved for the therapy of patients with advanced ER-positive breast cancer, there are now a number of additional experimental agents in clinical development, including pan-PI3K inhibitors and PI3K/mTOR inhibitors. Among them, buparlisib is being studied in two large phase III studies in combination with fulvestrant in patients with advanced disease. More recently, PI3KA-specific inhibitors have shown remarkable clinical activity in the phase I setting in patients with breast tumors that harbor PI3KA mutations, and it is anticipated that these agents will enter soon into phase II.
In summary, there is ample evidence that PI3K inhibition will be a fruitful approach in the treatment of patients with advanced breast cancer, and it is likely that determining the presence of PI3KA mutations in breast cancer will become useful in daily clinical practice.