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.