Rugo Offers Window Into Evolving Views of ER-Positive Disease

Beth Fand Incollingo
Published Online: Friday, September 6, 2013
Dr. Hope Rugo

Hope Rugo, MD

Research efforts are under way to improve the efficacy of hormone therapy in the management of advanced estrogen receptor-positive (ER) breast cancer, including new strategies for targeting the PI3K/ mTOR pathway.

During the 12th International Congress on the Future of Breast Cancer, Hope Rugo, MD, tackled this question: Which patients with ER-positive disease should receive PI3K/mTOR blockade as a way to reverse resistance to, or enhance the efficacy of, hormone therapy?

A professor of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, Rugo focused her talk on clues generated by the research community about the ideal patient population for the recently approved mTOR inhibitor everolimus and similar drugs in development, while also highlighting the mysteries that still cloud this issue.

Also during the conference, held July 18-20 in Huntington Beach, California, Rugo shared details about guidelines for the treatment of advanced breast cancer set by an international consensus panel, of which she was a member, in 2011.

Her presentation came as the panel readies to update those initial guidelines in November.

In an interview with OncologyLive during the conference, Rugo summarized key points of her talks and looked ahead at other promising developments in breast cancer treatment.

Q: How are investigators trying to learn which patients are most likely to benefit from PI3K/ mTOR blockade? What data are available so far?

A:
Our current research path stemmed from a failed first-line study, the phase III HORIZON trial1 of letrozole with or without mTOR inhibitor temsirolimus, published this year by Antonio Wolff in the Journal of Clinical Oncology, showing that there wasn’t a benefit from temsirolimus in patients with ER-positive locally advanced or metastatic breast cancer.

Those results raised some questions: Was the lack of efficacy of temsirolimus dosage-related, was it the schedule, was it the drug itself, or simply that mTOR inhibition wouldn’t help in ER-positive breast cancer? So, we followed up with a phase II neoadjuvant trial, Study 22222, of letrozole with or without everolimus, and saw a benefit from the addition of everolimus: a decrease in Ki67 and improved clinical response. Despite having serial tumor samples, detailed analyses of downstream markers were not able to identify a biologic marker that predicted response to neoadjuvant everolimus.

Given the lack of a defined predictive marker, the phase III BOLERO-23 trial of exemestane with or without everolimus was designed to rely on clinical criteria to choose the patients with HR [hormone receptor]-positive breast cancer who were most likely to have activation of the PI3K pathway. A number of studies have suggested that cancers that have been treated with hormone therapy and then recurred have a greater frequency of mutations in PI3K. BOLERO-2 enrolled patients whose cancers had previously been treated with nonsteroidal aromatase inhibitors, and that strategy actually panned out. Treatment with everolimus resulted in better progression-free survival, with more than a doubling in time.

Then, as a prospective planned study, tissue samples were collected from a subset of the patients in BOLERO-2, whose outcomes reflected those of the overall group. NextGen sequencing was done on those tumor samples, and different pathways were analyzed, including PI3K. It turned out that almost half of the tumors had a mutation in PI3K and the rest had less-common mutations that included cell cycle pathway markers as well as fibroblast growth factor receptor and others. Despite these individual mutations, all patients benefited from the addition of everolimus, which was quite curious. It didn’t matter whether the patients had an activation in the PI3K pathway or not.

In addition, the small subset of patients whose tumors had mutations in multiple pathways seemed to have the worst overall outcome, and did not benefit from the addition of everolimus. This is intriguing, and suggests that we could identify a subgroup of patients who require additional targeted therapy and should be considered for enrollment in clinical trials.

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