Overcoming Resistance to Endocrine Therapies

Ruth M. O'Regan, MD

Patients with hormone receptor-positive metastatic breast cancer (MBC) frequently respond to multiple lines of endocrine therapy but, unfortunately, resistance eventually develops. Research has revealed that signaling through alternate growth factor signaling pathways contributes to resistance, and a number of clinical trials have evaluated combination regimens targeting both estrogen receptor and growth factor signaling pathways.

At the 2011 School of Breast Oncology, Ruth M. O’Regan, MD, professor and vice-chair for Educational Affairs, Department of Hematology and Medical Oncology, at Emory University, Atlanta, Georgia, reviewed results from key trials investigating the utility of these regimens in patients with hormone receptor-positive MBC. The School of Breast Oncology was held at the university in November.

Some of the first studies looked at targeting the HER2 receptor in combination with hormonal therapy. The TAnDEM trial compared anastrozole with or without trastuzumab in patients with HER2-positive, hormone receptor-positive MBC. The addition of trastuzumab doubled progression-free survival (PFS) from 2.4 months to 4.8 months (P = .0016). According to O’Regan, the low PFS observed with anastrozole alone “shows that some of these cancers are resistant to hormonal therapy.”

A second trial evaluated letrozole with or without lapatinib as firstline therapy for hormone receptor-positive MBC, and included both HER2-positive and HER2-negative patients. “In the intent-to-treat population we see about a month difference in PFS, but it is driven completely by the HER2-positive group. In that group, by adding lapatinib to letrozole, you improved PFS by 5 months,” O’Regan said. (Table)

Several studies have also looked at adding an mTOR inhibitor to endocrine therapy. The randomized phase II TAMRAD study compared tamoxifen with or without everolimus in patients with hormone receptorpositive MBC who had previously been exposed to aromatase inhibitors. Everolimus increased the clinical benefit rate from 42% to 61%, and time to progression was improved from 4.5 months to 8.6 months.

“What was very interesting here was that even though this was a small study, the researchers broke it down based on clinical criteria to see whether patients had primary or secondary hormone resistance, and the benefit of adding everolimus was seen predominantly in the patients with secondary hormonal resistance,” O’Regan noted.

Preliminary results from the BOLERO-2 trial were recently presented at the European Society for Medical Oncology conference in September 2011. This phase III trial randomized postmenopausal patients with estrogen receptor-positive, HER2-negative advanced breast cancer refractory to letrozole or anastrozole to exemestane plus everolimus or placebo. The addition of everolimus increased PFS from 2.8 months to 6.9 months (P = 1.4 x 10-15). “There is a wide separation of the curves in favor of everolimus,” O’Regan said, and “the P value is one of these highly, highly, highly significant P values.”

Finally, a new area of investigation is the combination of histone deacetylase (HDAC) inhibitors with endocrine therapy. According to O’Regan, “there is a lot of preclinical data suggesting these agents may be important in hormone receptor-positive and hormoneresistant breast cancers.”

The randomized phase II ENCORE 301 trial evaluated exemestane plus the HDAC inhibitor entinostat or placebo in postmenopausal women with estrogen receptor-positive MBC that had progressed on a nonsteroidal aromatase inhibitor. Preliminary results demonstrated a 2-month improvement in PFS with the addition of entinostat. O’Regan said this combination may be going into a phase III trial, although it was still in the process of being designed.

These results are promising, and combination regimens will likely add to the treatment armamentarium for hormone receptor-positive MBC in the future. Such approaches may offer patients the hope of delaying resistance and prolonging the time that endocrine therapy is effective.