Dual strategy promises to overcome endocrine resistance

SAN ANTONIO-Combining endocrine therapy with signal transduction inhibition is an effective means of overcoming endocrine resistance in at least some populations of patients with breast cancer. Stephen R.D. Johnston, MA, PhD, director of clinical research and development at the Royal Marsden Hospital in London, discussed the data on this emerging strategy during an SABCS plenary lecture.

"Current endocrine therapies for women with estrogen-receptor–positive breast cancer have led to substantial improvements in outcomes," Dr. Johnston said. "But their success is limited by either initial de novo resistance or subsequent acquired endocrine resistance."

With insight from molecular biology, it has become clear that there is complex cross-talk, both genomic and nongenomic, between estrogen receptors and growth factor receptors when it comes to intracellular signaling.

"With these complex pathways, we start to understand how we can use drugs to interfere with this [cross-talk] and perhaps prevent and reverse [endocrine] resistance," he said.

An important take-home message coming out of preclinical and clinical studies is that breast cancers with acquired endocrine resistance often still express estrogen receptors, although their function may be altered, Dr Johnson said. In addition, patients with such resistance often have enhanced signaling in the epidermal growth factor receptor (EGFR) and HER2 pathways.

Clinical data on dual inhibition of estrogen receptors and growth factor receptors in breast cancer are somewhat limited and present a mixed picture, Dr. Johnston noted.

In the phase III TAnDEM trial, patients with HER2-positive, hormone-receptor–positive metastatic breast cancer had significantly better progression-free survival if given anastrozole plus trastuzumab instead of anastrozole alone (4.8 versus 2.4 months).

In another phase II trial, women with metastatic breast cancer who had received no endocrine therapy at all or none recently had a nonsignificantly longer time to progression when given gefitinib plus tamoxifen than when given tamoxifen alone: 10.9 versus 8.8 months (SABCS 2007 abstract 2067).

And in another phase II trial, women with estrogen-receptor–positive metastatic breast cancer had significantly longer progression-free survival when given anastrozole plus gefitinib than when given anastrozole alone, 14.5 versus 8.2 months (ASCO 2008 abstract 1012).

The largest trial to date evaluating the dual inhibition strategy, EGF30008, is comparing first-line therapy with letrozole plus lapatinib with letrozole alone in women with locally advanced or metastatic breast cancer. It's important to note that the trial included women with differing HER2 status and stratified women according to prior adjuvant endocrine therapy, Dr. Johnston said. Results from EGF30008 will be presented at SABCS 2008 (abstract 46).

Four neoadjuvant trials have compared endocrine therapy alone with endocrine therapy plus signal transduction inhibitors (erlotinib, gefitinib, or everolimus) and have assessed associations of molecular responses with clinical and pathological responses.

"If we can take any lessons from these studies, it is about selecting the patients who will derive the benefit [by using] the biopsies in the studies, particularly when we go forward to do the large randomized trials," Dr. Johnston said.

Taken together, the existing evidence provides proof of the concept that signal transduction inhibitors that target growth factor receptors not only inhibit the growth of breast cancer, but can also restore endocrine sensitivity.

"The challenge is to identify those patients [who may benefit] and which oncogene pathways they are going to use in the development of their resistance," he said.

Finally, when it comes to designing new trials of dual therapy, it will be crucial to attend to patients' prior endocrine treatment and current endocrine resistance status.