Overcoming Resistance to CDK4/6 Inhibition in ER+ Breast Cancer

Estrogen receptor (ER)-positive tumors in breast cancer have longer treatment responses when CDK4/6 inhibitors are added to standard hormone therapy compared with hormone therapy alone. However, research oncologists are still observing responses in patients with resistance to CDK4/6 inhibitors to better understand how outcomes can be improved.

New therapeutic approaches have been introduced in the landscape of ER-positive breast cancer. Some of these therapies can reactivate CDK4/6 activity in patients, while others lead to inactivation of the RB gene or upregulation of mitotic kinases.

In an interview with Targeted Oncology, Sarat Chandarlapaty, MD, PhD, physician-scientist, the Sarat Chandarlapaty Lab, Memorial Sloan Kettering Cancer Center, explained the mechanisms of resistance to CDK4/6 inhibitors. He also discussed new therapeutic strategies are being curated and implemented to overcome resistance in patients with ER-positive breast cancer.

TARGETED ONCOLOGY: Can you give your take on the mechanisms of resistance to CDK4/6 inhibitors and new therapeutic approaches?

Chandarlapaty: CDK4/6 are extremely effective. While we’re studying resistance because of what we see in the clinic, if we forget how effective they are, we’ll do a disservice to the patients and limit the ability to overcome resistance. Sometimes you have to consolidate an effect rather than just trying to change gears entirely.

The types of things that we’re seeing clinically, in terms of resistance mechanisms, can be split into 2 main categories. One category includes those mechanisms that lead to reactivation of 4/6 activity, for example high CDK6 or high CDK2. The implication of that is to try and hit this harder and develop a new drug against CDK6 or CDK2. The second category includes drugs that bypass these drugs and might lead to loss of RB or upregulation of mitotic kinases. Targeting, in this case, would be fundamentally different because you may have to inhibit those mitotic kinases or apparent transcription. These 2 classes have different implications for overcoming resistance.

We now have to integrate everything we’ve learned on this topic to how we continue to treat. If there is some cancer that is resistant and some that is sensitive and we deal with the only that resistant cancer, then sensitive cancer might come back up. We have to deal with complex disease states through combination therapy.

TARGETED ONCOLOGY: How are challenges with therapies for patients with CD4/6 resistance being address right now?

Chandarlapaty: What we are trying to learn is whether or not we can develop more potent inhibitors of CDK2 and CDK6 and whether we can use those in combination with the existing therapies in ways that are not too toxic. For the bypassed tumors, we are trying to study when those exist, if they co-exist within minor populations that grow out after time. Others are developing drug to work in that space.

The other challenge is understanding the complex burden of disease that exists. We’re attempting to develop tools to help us to granularity on the full spectrum of disease so that we don’t just employ approaches that only deal with a part of the disease.

TARGETED ONCOLOGY: Are there currently any markers for traits that you look for in patients before recommending them for treatment with CDK4/6 inhibitors?

Chandarlapaty: Fortunately, this is currently the frontline standard. All the patients who have ER-positive breast cancer are candidates for upfront treatment with a CDK4/6 inhibitor. Recent studies that have been presented at conferences showed overall survival benefits for that approach over hormone therapy alone. Next, we’re trying to investigate whether we should give a different type of hormone therapy based on our profiling, as a companion with CK4/6 inhibitors.

TARGETED ONCOLOGY: How is genetic testing being implemented for treatment considerations?

Chandarlapaty: Currently, genetic testing is used for a couple of reasons in metastatic breast cancer. First, the identification of the PIK3CA mutation will allow the subsequent use of a PI3K inhibitor, alpelisib (Piquray). We don’t always use it first but as our second-line therapy, and that’s while we profile patients.

Beyond that, there are some rare alterations that are also worth testing to identify and track mutations for treatment with NTRK inhibitors, microsatellite instability status for checkpoint blockade therapies, and germline mutations in BRCA1 and BRCA2 for treatment with PARP inhibitors. All of that information can be gained by doing some form of genomic profiling.