Cristofanilli Calls for More Effective Options in ESR1-Mutant Breast Cancer

Massimo Cristofanilli, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Massimo Cristofanilli, MD

Despite advances made in disease biology and detection, treatment for patients with ESR1-mutated, estrogen receptor (ER)—positive, HER2-negative breast cancer continues to be an area of unmet need, according to Massimo Cristofanilli, MD. As more patients develop resistance to available agents, he adds, the need for novel safer and more effective therapies is emphasized.

“These ESR1 mutations are present in approximately 40% of patients, and currently, [their presence] is associated with predictive information. If you know a patient has an ESR1 mutation, then you should not use or expect any benefit from aromatase inhibitors,” said Cristofanilli. “Most of the time, we will use the only other drug that is available, which is fulvestrant (Faslodex). However, we know that the drug…is not able to overcome some of the resistance associated with this mutation.”

To address these resistance challenges, new agents and combinations are being explored. One such agent is the nonsteroidal selective ER modulator lasofoxifene, which has shown preclinical promise when used in combination with palbociclib (Ibrance) in postmenopausal patients with endocrine therapy—resistant, locally advanced or metastatic ER-positive, HER2-negative breast cancer whose tumors harbor ESR1 mutations.

In May 2019, the agent received a fast track designation from the FDA for this patient population. The agent is currently under investigation in the open-label, randomized, multicenter phase II ELAINE trial (NCT03781063) comparing its use with fulvestrant in patients with advanced or metastatic ER-positive, HER2-negative breast cancer that is ESR1-mutant.

In an interview with OncLive^®, Cristofanilli, a professor of medicine at the Northwestern University Feinberg School of Medicine, of Northwestern University, discussed emerging treatment approaches for patients with ER-positive/HER2-negative breast cancer with an ESR1 mutation.

OncLive: What treatment options are available for patients with ER-positive, HER2-negative breast cancer?

Cristofanilli: Metastatic breast cancer is now treated on the basis of subtypes. The most common disease subtype is the ER-positive tumor. For these patients, many treatments have been developed. Primarily, [we are] combining endocrine therapy—for example, selective ER degraders and aromatase inhibitors (AIs)—with CDK4/6 inhibitors. [By using] a molecular test, we have identified some mechanisms of resistance. One of them is very important because it is becoming more common than it was in the past; it's the evidence of mutations in the ER itself.

Could you speak to the unmet need in this space?

This is an incredible area of need. Our patients receive multiple lines of endocrine therapy over the course of their lifetime, and when they experience recurrence, we essentially only have 2 [options]: one of the AIs or fulvestrant. We are very much limited [in terms of] the type of endocrine agent that we can combine with new therapy.

For example, with regard to the CDK4/6 inhibitors, we have three agents being used with endocrine therapy in the first-line and recurrent settings. We also have the [somewhat] recent approval of the PI3K inhibitor alpelisib (Piqray). Unfortunately, we don't have any more agents to combine with future targeted therapies, simply because after [a patient] progresses on fulvestrant, there are no other drugs [available]. There is an absolute need for the development of new agents.

What is the profile of a patient with ER-positive, HER2-negative disease who progresses on frontline therapy? What does their prognosis look like?

There are several features [that we associate with] these patients. We often see that younger patients are developing breast cancer at an early age; some of them also have ER—positive disease. These patients are usually treated with tamoxifen as an adjuvant treatment.

In the past 5 to 10 years, patients have also been exposed to AIs as part of their adjuvant treatment as a way to block estrogen ovarian function. The majority of patients either become postmenopausal, have been exposed to tamoxifen and an AI, or an AI for some time. The postmenopausal patients receive this treatment for at least 5 years. Usually these patients initially [experience] recurrence in the bones; which are the primary site of recurrence in ER-positive disease.

At the same time, there is a population of these patients, for a reason that we don't know, who recur very early on. These patients also have visceral metastases, for example, to the liver. We have found recently that when patients have an [ESR1] mutation, they are more likely to develop an aggressive tumor with liver metastases. Therefore, I believe it's clear that [ESR1] mutations are not only predictive of lack of efficacy [to AIs], but [their presence is] also becoming more of a prognostic factor. That is another reason why we need to develop new agents.

What efforts are being made to address this patient subgroup?

There are a number of agents, at least 3 or 4 that have been developed with different purposes. Of course, the overall objective is to develop an agent that will eventually be effective in those who are resistant to endocrine therapy, and primarily in those [with ESR1] mutations. However, this avenue is very difficult simply because the standard of care has changed.

We’re finding it less and less possible to use a single agent in the metastatic setting. As such, we need to anticipate that some of these agents will benefit from [being used in] combination. For example, if [a patient receives] fulvestrant with one of the CDK4/6 inhibitors [and progresses], the idea is that we need to change the CDK4/6 inhibitor and either go to an agent that targets PI3KCA or maybe [explore] another combination with an agent that is not cross-resistant. The problem is that, if a patient has an [ESR1] mutation and has progressed on fulvestrant, they do not have an endocrine companion. I [believe] this is the setting in which you will be likely to combine a new agent. For example, if you have a patient with endocrine-progressive disease who has an [ESR1] mutation, combining [a new agent] with either a CDK4/6 inhibitor or a PI3K inhibitor [in the first-line setting] would be the ideal [space to do so].

Could you speak to the data seen with the investigational agent lasofoxifene?

Most of the [research with this agent] is ongoing. We have seen some indication that the estrogen is degraded, and that the [ESR1] mutation may be able to disappear in the tissue in the blood [with this agent]. We have seen in the first phase of this clinical trial that the toxicity profile [of lasofoxifene] is very tolerable. Because it is an oral agent, it may have some associated gastrointestinal symptoms, but they are easy to [manage]. The goal is to complete these studies and have a good signal and indication of efficacy. I believe this will be possible in the next 8 to 12 months, because these are small studies.

What are your thoughts on the agent receiving fast track designation by the FDA? If approved, how could it impact treatment for these patients?

If that agent were to be approved, it will have a large use in the clinic. We need to educate physicians on what the value of an [ESR1 mutation] is and why we need to use such an agent after progression on fulvestrant. At the same time, there should be a plan for developing combinations, because I'm sure that the FDA will require [a plan] before we actually use this agent across the board in many situations following [progression on] fulvestrant. [We] want to see that [agent] in combination with some of the CDK4/6 inhibitors. [Lasofoxifene] has been granted [fast track designation by the FDA] and has great [potential] to demonstrate benefit in these patients. We are all looking forward to contributing to the development of this agent.

Where will future research efforts in this disease space focus?

The particular identification of this mutation in an earlier phase is becoming more important. If we assume that this resistance develops during the adjuvant phase before becoming metastatic, we are developing more sensitive technology to detect tumor in the blood. Therefore, we could identify this mutation very early on.

Then, once you identify a mutation of resistance, the question becomes, “Would you start the drug that you already know [patients are somewhat resistant] to and cannot eliminate this disease, or will you go to another agent?” To me, this new agent will have a [role], not only in the established metastases, but hopefully, also earlier on in micrometastatic disease.

Muriel L, Fanning SW, Greene M, et al. Lasofoxifene as a potential treatment for ER+ metastatic breast cancer. J Clin Oncol. 2019;37(15 suppl; abstr 1056). doi: 10.1200/JCO.2019.37.15_suppl.1056.