Strategies Needed to Overcome Drug Resistance in Breast Cancer Subset

Optimizing treatment for patients with HR-positive breast cancer means that researchers must first find a way for patients to overcome drug resistance, says William J. Gradishar, M.D.
BY ANDREW J. ROTH
PUBLISHED: SEPTEMBER 27, 2016
Combining and sequencing novel targeted therapies, such as CDK 4/6 inhibitors and PI3K inhibitors with anti-hormonal therapies will be a key factor in helping patients with hormone receptor (HR)-positive breast cancer overcome drug resistance. Then, physicians can focus on optimizing treatment for these patients, says William J. Gradishar, M.D.
 
Gradishar addressed this topic in a presentation at the Lynn Sage Breast Cancer Symposium hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  
 
Gradishar is the deputy director of the Lurie Cancer Center Clinical Network and director of the Lurie Cancer Center’s Maggie Daley Center for Women's Cancer Care in Prentice Women's Hospital.  
 
CURE sat down with Gradishar to discuss his talk.
 

Can you provide me with a brief overview of your talk?

The talk focused on HR-positive breast cancer and the strategies that have been employed to enhance the effect of standard anti-hormonal therapy and the strategies to overcome resistance that develops.  
 
This has taken us into the realm of combining endocrine therapies with targeted therapies: mTOR inhibitors, such as Afinitor (everolimus), and CDK 4/6 inhibitors such as Ibrance (palbociclib) and others that are in development.  
 
Additionally, there has been a lot of work and interest in looking at PI3K inhibitors because that pathway is amplified and mutated in patients with estrogen receptor (ER)-positive breast cancer. The strategy would be to look at a combination of anti-hormonal therapy and a PI3K inhibitor and see if that improves response and translates into a better overall outcome. We are also evaluating drugs that affect epigenetic phenomena using HDAC inhibitors, such as entinostat.  
 
To date, we know that adding an anti-hormonal therapy adds time to when the disease progresses. We're hopeful that as we go forward some of these other drugs may have the same effect. Some of these drugs are being investigated in early-stage breast cancer to see if similar strategies might translate into a better overall outcome.

What are the challenges associated with treating patients after disease progression?

It's inevitable that patients with metastatic disease will develop progressive disease. All of the therapies we have —even beyond anti-hormonal therapy — despite good responses, the disease figures out a way of working around the treatment. There are a number of reasons why that may occur: the tumor can evolve, mutations can develop, bypass pathways can become more dominant, and subclones of tumor cells may be more responsive to one therapy versus another. This speaks to the issue of having more strategies when progression happens.  
 
The hope would be that by having other agents that can be combined with anti-hormonal therapies, that you may be able to suppress or delay those resistances. The ultimate goal with anti-hormonal therapy is to continue it as long as possible because compared with chemotherapy, it's much better tolerated.

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