Hope Rugo, MD
Although hormone-targeting therapies have been a long-established strategy for the treatment of estrogen receptor (ER)-positive breast cancer, more than 20% of patients with early-stage disease relapse and those who progress to a metastatic stage eventually die from their illness.1
Research efforts to identify mechanisms of resistance to therapy and develop novel agents and combinations to attack those networks are producing tangible results that have translated into fresh options in clinical practice. The FDA has approved several new agents for this patient population in recent months and expanded the indications of previously approved drugs.
Resistance to endocrine therapy in patients with ER-positive breast cancer is defined in 2 ways 2 :
- Primary resistance: recurrence within adjuvant therapy or disease progression less than 6 months after treatment
- Acquired resistance: recurrence at least 12 months after completion of adjuvant therapy or progression 6 months or more after the initiation of endocrine therapy in the metastatic setting
Several key mechanisms of endocrine resistance have been identified, including the PI3K/AKT/ mTOR growth factor signaling network, cyclindependent kinase (CDK) signaling, and histone deacetylase (HDAC) activity. Strategies aimed at these processes have been among the most active attempts to boost the efficacy of endocrine therapies (Figure).1,2
Figure. Targeting Endocrine Therapy Resistance
Ingrid A. Mayer, MD, MSCI, co-leader and clinical director of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center, distinguished between mechanisms of primary and acquired resistance during a presentation at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in June.2
For example, primary resistance may be driven by CDK amplification or expression while activation of growth factor signaling and mutations in the ER pathway are associated with acquired resistance.2
Mutations in the ESR1 gene, which encodes ER-alpha, have been reported in 11% to 55% of recurrent or metastatic cancers that have progressed after long-term endocrine therapy, Hope S. Rugo, MD, and colleagues noted.1
“The development of ESR1 mutation following endocrine therapy provides further evidence that ER remains relevant in resistant tumors. Combination strategies that target both ER and resistant pathways are therefore rational approaches to overcome endocrine resistance,” the authors wrote. They said that cost and toxicity would increase with the addition of targeted therapies.
In her ASCO presentation, Mayer stressed the need for new approaches to circumvent resistance by preventing progression and more effectively treating metastatic disease. She noted that some new therapies have been effective at delaying disease progression but that “people still die of metastatic disease.”
“We have very effective therapies for ER-positive metastatic breast cancer, there’s no question about that,” Mayer said. “But we don’t know yet if these therapies are needed at all times. A lot of the ongoing trials are trying to answer whether we are going to sequence or combine all these approved or to-beapproved targeted [therapies] in everybody and what is going to be the cost of that not just financially but obviously from a side effect and tolerance point of view. My answer to that is, we don’t know yet.”
The development of CDK4/6 inhibitors has been an area of rapid growth in the breast cancer field in the past several years and 3 agents are now approved that employ this approach: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).