Improving Endocrine Therapy for Breast Cancer: It's Not That Simple

Endocrine therapy is the mainstay of treatment for estrogen receptor (ER)-positive breast cancer and often represents the first several lines of treatment in the metastatic setting. Unfortunately both de novo and acquired resistance to endocrine therapy remain important clinical problems, and recent efforts have centered around strategies to combat this resistance. Preclinical studies implicate crosstalk between ER and critical signaling pathways, such as the epidermal growth factor receptor/human epidermal growth factor receptor 2 (HER2) and extracellular signal-regulating kinase 1/2/mitogen activated protein kinase cascade and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, as key mediators of endocrine resistance. Focus on the PI3K/AKT/mTOR pathway has intensified recently, not only because PI3K-activating mutations are found in 36% of human breast cancers, but also based on preclinical studies associating activation of the PI3K/AKT/mTOR pathway with endocrine resistance, and correlating mTOR inhibition with sensitivity to endocrine therapy in cell lines. In addition, estrogen deprivation increases apoptosis following PI3K inhibitor treatment, providing a rationale for combined therapy even in endocrine-sensitive disease. For all of these reasons inhibition of the PI3K/mTOR pathway, both alone and in combination with antiestrogen therapies, is an active area of research in the treatment of ER-positive disease, which still kills more women than any other breast cancer subset. Clinical testament to the value of cotargeting ER and the PI3K/ AKT/mTOR pathway comes from several key papers. In the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2), a randomized phase III study of 724 postmenopausal women with hormone receptor (HR) –positive, HER2-negative metastatic breast cancer that had progressed on therapy with a nonsteroidal aromatase inhibitor (AI), combination therapy with exemestane and the mTOR inhibitor everolimus resulted in significantly longer progression-free survival (PFS; 7.8 months v 3.2 months) and higher response rate than singleagent exemestane. In the Tamoxifen and RAD001 (TAMRAD) study, a smaller randomized phase II trial in a similar patient population, patients receiving the combination of tamoxifen and everolimus had a higher clinical benefit rate (61%) and longer time to progression (8.6 months) than the group receiving tamoxifen alone (42% and 4.5 months). In that study, patients with secondary resistance to AI seemed to benefit more from the combination than patients with primary resistance, supporting the concept that cross-talk between pathways and the sequential upregulation of the PI3K/mTOR signaling is a mechanism of resistance. While these two studies each used a different endocrine agent, they were otherwise similar in several key respects: the population studied had evidence of acquired AI resistance, both used the mTOR inhibitor everolimus, and improvements in clinical end points were similar, prompting the US Food and Drug Administration to approve everolimus for second-line treatment of HR-positive breast cancer in July 2012. However these benefits were not without toxicity; in both studies combined everolimus/endocrine therapy had substantially higher stomatitis (56%), rash (36% to 44%), fatigue (33% to 72%), diarrhea (30% to 39%), and anorexia (29% to 43%) than single-agent endocrine therapy. Given real toxicity and substantial cost ( $5,000 per month), clinical decision making regarding the addition of everolimus to endocrine therapy is generally made on a case-by-case basis. In the article accompanying this editorial, Wolff et al examine the combination of the nonsteroidal AI, letrozole, and the mTOR inhibitor, temsirolimus, in the first-line treatment of metastatic breast cancer. This study, called HORIZON, was a large multicenter multinational randomized phase III trial involving 1,112 patients, that found no benefit in PFS associated with adding the mTOR inhibitor to AI therapy. Indeed, the trial was stopped for futility by the independent data monitoring committee. Response rate and overall survival were also similar between groups. Interestingly, although the combination arm had higher incidence of expected mTOR inhibitor–related toxicity than the single-agent arm, the occurrence of these toxicities was lower than that seen in the everolimus studies described above. For example only 14% of patients experienced mucositis, 15% rash, and 21% diarrhea. In a subgroup analysis, the authors found that patients 65 years old and younger appeared to benefit from the combination therapy whereas older patients did not. This exploratory but provocative finding was not seen in the subgroup analyses by age in BOLERO-2, and the median age was similar in both studies. Why would these large trials of combination therapy with mTOR inhibitors and AIs yield discordant results? One key difference is that the patient population in the HORIZON study was largely AI-naive and temsirolimus/letrozole was the first endocrine treatment for metastatic disease. By contrast, patients in both BOLERO-2 and TAMRAD had AI-resistant disease. In BOLERO-2, 84% had initially endocrinesensitive disease and then progressed on an AI, so this population was essentially the same secondary resistance population that showed the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 2 JANUARY 1