Bypassing Endocrine Resistance in Advanced HR+ Breast Cancer

Christopher R. Chitambar, MD, FACP

Treatment for patients with metastatic hormone receptor (HR)—positive, HER2-negative breast cancer depended on blocking the estrogen receptor (ER), until research showed that cancer proliferation was possible independent of the ER, explained Christopher R. Chitambar, MD, FACP.

“More recently, we’ve researched other mechanisms that might be turning on ER-positive breast cancer proliferation, either through the ER or via other signaling mechanisms and modifiers,” said Chitambar.

The most well-known mechanism that has borne clinical utility is the cyclin D cell signaling pathway, and research exploring this pathway has led to the development of the 3 FDA-approved CDK4/6 inhibitors, palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).

Additional insight into the mechanisms that drive proliferation led to the development of alpelisib (Piqray), the first PI3K inhibitor approved for use in combination with fulvestrant (Faslodex) as a treatment for postmenopausal patients with PIK3CA-mutated, advanced breast cancer after progression on or after an endocrine-based regimen.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Chitambar, a professor at the Medical College of Wisconsin, discussed the research that led to the development of CDK4/6 inhibitors in metastatic HR-positive, HER2-negative breast cancer and the significance of the PI3K inhibitor alpelisib.

OncLive: Could you discuss how the CDK4/6 inhibitors led to a paradigm shift in the field of metastatic HR-positive, HER2-negative breast cancer?

Chitambar: For several decades, we've been aware of the role of the ER in stimulating breast cancer cells. The ER is the stimulus, the switch, and the fertilizer that feeds breast cancer. We've known that blocking the ER or lowering the level of estrogen in the body was the primary strategy for treatment. We would use drugs such as tamoxifen, aromatase inhibitors (AIs), or fulvestrant to degrade the ER. That has been the mainstay of treatment for many decades. However, many patients will escape this blockade and their tumor will grow.

We know that the receptors may be activated independent of estrogen through other pathways, such as HER2, insulin-like growth factors, and other factors. Additionally, there may be mutations in the receptor. There also may be other pathways downstream that can subsequently get turned on that completely bypass that. Then, all cells that are dividing and proliferating have to go through a cell cycle. There, we’ve learned that one of the targets called cyclin D may be increased or hyperactivated in proliferating cells, particularly in breast cancer.

With that background, there has been a lot of preclinical research looking at drugs that target the cell cycle and drugs that might turn off these pathways. We have 2 main categories that are evolving. One is the CDK4/6 inhibitors, which block the cell cycle. We have a riches situation where we have not 1, but 3, inhibitors out there. One is palbociclib, which was the first one on the block. We also have ribociclib, and then, most recently, abemaciclib. Each one of these [inhibitors] seem to be equal when it comes to antitumor activity.

The first trial that was generated by animal and cell culture studies with palbociclib was the PALOMA-1 trial. These studies showed that when you combined palbociclib with an anti-estrogen therapy, you got synergy. Tumors that were formally resistant to anti-estrogen therapy became sensitive. In effect, we were bypassing drug resistance or anti-estrogen blockade. That was very exciting. This was rapidly translated to the PALOMA-2 and -3 clinical trials. The combinations were of nonsteroidal AIs, such as anastrozole or letrozole, plus palbociclib. All of these studies had placebo controls. All of these studies showed superiority and prolongation of disease-free survival (DFS), no matter which way you looked at it.

Next in line came the MONALEESA trials, which were very similar in that they showed a consistent DFS prolongation with, in this case, ribociclib plus an anti-estrogen agent. The same is true of abemaciclib. These studies differ somewhat in the timing, specifically in terms of whether they're first-line or second-line therapies, but all of the results show a similar benefit.

They also differ in terms of their toxicity profile. For example, palbociclib and ribociclib are more myelosuppressive, and therefore, have to be given 3 weeks on/1 week off, whereas abemaciclib can be given continuously. There, you run into other gastrointestinal toxicities, such as diarrhea and fatigue; it's a different profile. We have choices; however, we don't quite understand how to sequence these agents. Those are things to be tested. For example, would you start with fulvestrant and one of the CDK4/6 inhibitors, or would you start with an oral combination where you're using an antiestrogen, such as an AI? We have not really looked at that situation. What about tamoxifen? Will these be equally effective in combination with tamoxifen?

The MONALEESA-7 trial was designed to look at the issue in premenopausal women. The investigators wanted to test the safety as well as the efficacy [of CDK4/6 inhibitors in this population]. In this trial, women were made postmenopausal by receiving ovarian suppression. They showed that it was effective, but this was a premenopausal population where the biology of breast cancer is very different from that of postmenopausal women.

How will the FDA approval of alpelisib shift the paradigm?

One of the more recent things is the soon-to-be-available alpelisib, which targets mutations in the PIK3CA gene. It turns out that about 40% of patients with ER- or HR-positive breast cancer have these mutations that drive cancer proliferation. In the studies that were recently published, the combination of alpelisib with fulvestrant shows clear superiority versus placebo. We're excitedly awaiting the approval of this trial based on data from the SOLAR-1 trial.

When alpelisib is approved, it will serve as another tool in our toolbox for patients who have the PIK3CA mutation; it will also allow us a few additional tools or strategies for diagnosis. In other words, circulating [tumor] DNA is available now to check for mutations. I believe that’s going to be from peripheral blood draws, so we won’t have to go back to tumors or rebiopsy. That’s going to be a great step forward. The ease of [that approach] and the sensitivity of it will allow us to identify these patients. It's also going to be important for our pathologists to learn that when we generate a report, we've got to do more than just report ER, progesterone receptor, and HER2. Now, we’ll need to add in information on these mutations—these other biomarkers. That's going to broaden the way we do business, not just in treatment but also in diagnostics.

Could you expand on the potential survival benefit seen in the PALOMA-3 trial?

When we went back and looked at [PALOMA-3], what became clear was the survival benefit in patients who previously responded to antiestrogens and then had stopped responding. That's why I believe switching [therapy may be warranted]. Before we had the CDK4/6 inhibitors at our disposal, we would start with the AIs. If the patient progressed, we would switch among the AIs, so if you went from anastrozole to exemestane there was a benefit. If you went from there to fulvestrant, there was potentially another gain. These are small gains but real gains.

Prior sensitivity to an anti-estrogen does impact subsequent sensitivity to another anti-estrogen, which is sometimes forgotten. The thinking, at least in my mind, should be that we should try to exhaust the various combinations before moving forward. Yes, it's always nice to have data, but if you consider the various permutations that one could try, we would never have [the resources to conduct these trials]. There's just not enough time and money for them. If I had to make a decision tomorrow, I can't tell a patient to come back in 5 years when the trial is mature. Medicine is still very much an art when we are making these choices.

If patients don’t respond after 1 month on therapy, should clinicians consider stopping therapy?

With cytotoxic chemotherapy for example, we usually give 2 to 3 cycles. Patients could [receive the chemotherapy] 3 weeks apart and have a scan that shows that it's not working. Then, you may consider switching drugs. With the CDK4/6 inhibitors, you don't begin to maximize your benefit until about 4 months; the curves are very instructive. It’s premature to say the drug isn’t working if, after 2 months, there’s no change. As long as the tumor is not growing and patients are tolerating it, it's worth it to press on. I've actually seen that in my own practice, where we don’t see a change after 2 months. Patients express an element of despair, believing it's not going to work. [That’s not the case]; give it time. That's an important point [to remember], especially when we deal with patients with metastatic breast cancer who know the seriousness of the situation.

What other agents do CDK4/6 inhibitors have the potential of synergizing with?

The combinations are going to be quite interesting. Do you try something along the lines of an oral agent or an oral chemotherapy drug that's better tolerated—or, a modification of these 2? Much of our success in the treatment of patients with metastatic disease has come by mixing and matching. A case in point would be to look at the recent immunotherapies. When they were tried as single agents, everybody said, “Well, they were not working.” Now, we have 1 agent that's approved in combination with chemotherapy [in triple-negative breast cancer].

We may be looking at a modification thereof or a mixture, if you will, of different steps along the way we could be using to block the ER and at the same time the cell cycle, potentially in a patient who has a PIK3CA mutation by adding in alpelisib. There are all these possibilities which is why we have to keep a very open mind. It's not unlike HER2-positive disease where patients are living longer with all these drugs that have allowed us to get away from chemotherapy completely. We're seeing this change and forward movement with these new drugs, which is really refreshing.

Editor’s Note: This interview took place prior to the FDA approval of alpelisib in combination with fulvestrant for postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic disease.