Expanding the Treatment Toolbox in ESR1-Mutant Breast Cancer

Daniel Stover, MD, discusses unmet needs in patients with ESR1-mutant breast cancer, his hopes for lasofoxifene in that setting, and ongoing research efforts examining novel agents and approaches in the pipeline.

Daniel Stover, MD

Although patients with estrogen receptor (ER)—positive, HER2-negative breast cancer who harbor ESR1 mutations currently have a poor prognosis, novel approaches are emerging in an effort to improve outcomes for this population, said Daniel Stover, MD.

“Multiple studies are ongoing in [metastatic ER-positive, HER2-negative breast cancer],” said Stover. “As a clinician, I am excited about the potential to add more agents to the tool belt for my patients with this disease.”

ESR1 mutations are usually detected in patients with metastatic ER-positive, HER2-negative breast cancer who have received prior treatment with an aromatase inhibitor (AI). Although fulvestrant (Faslodex) or selective ER degraders (SERDs) have demonstrated efficacy in some patients who progress on AIs, optimal systemic therapy after disease progression is currently unknown.

Investigators are addressing resistance challenges by examining new agents in clinical trials, such as the phase II ELAINE trial (NCT03781063) of the nonsteroidal selective ER modulator lasofoxifene.

In the trial, patients with advanced or metastatic ER-positive, HER2-negative breast cancer whose disease progressed on an AI in combination with a CDK4/6 inhibitor will be randomized to receive either lasofoxifene or fulvestrant. Investigators hypothesize that the agent will double the median progression-free survival versus fulvestrant in this patient population.1 Lasofoxifene received a fast track designation from the FDA in May 2019 for use in this patient subgroup.2

Molecular testing is an important component of care, according to Stover, but obtaining adequate samples via tissue biopsy can be difficult or risky in some patients. Liquid biopsy might offer a promising alternative.

“The use of liquid biopsy in metastatic breast cancer is increasingly promising,” said Stover. “We believe that with very sensitive assays, [ESR1] can be detected with very high sensitivity and with high confidence—even in patients with relatively low amounts of circulating tumor DNA (ctDNA).”

In an interview with OncLive, Stover, an assistant professor of medicine, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center—James, discussed unmet needs in patients with ESR1-mutant breast cancer, his hopes for lasofoxifene in that setting, and ongoing research efforts examining novel agents and approaches in the pipeline.

OncLive: What is the biology of ESR1-mutant breast cancer?

Stover: ESR1 mutations are DNA mutations in the ESR1 gene, which encodes the ER. [These mutations are] most common in [patients with] advanced or metastatic ER-positive, HER2- negative breast cancer. We know that ESR1 mutations are rare at the time of diagnosis and they are increasingly detected after patients have received treatment with an AI. We also know that patients who harbor an ESR1 mutation have a significantly worse prognosis than patients who have an ESR1 wild-type gene.

ESR1 mutations are primarily detected in [patients with] metastatic ER-positive, HER2-negative breast cancers. They can be picked up in other cancers, but that’s incredibly infrequent. Most of the ESR1 mutations that are detected are specifically in the ligand-binding domain of ESR1, and these mutations activate the ER gene constitutively. As such, the ER gene just continues to fire even if there’s no estrogen present; it’s continuously active. We believe that this not only drives growth of the cancer cells, but it may also change how they behave, their metastatic potential, and how estrogen signaling interacts with other signaling pathways, such as the insulin-like growth factor pathway.

What are some unanswered questions regarding the treatment of patients with ESR1 mutations?

We have identified that the ESR1 mutation—carrier population have a worse prognosis and that they exhibit resistance to AI therapy. However, what the appropriate next therapy [should be for these patients] remains unclear. These patients seem to be sensitive, in some cases, to fulvestrant or SERDs. However, we still have a lot to learn about the optimal therapy and timing of therapy for these patients.

What are the pros and cons to using a degradation versus blockade approach in these patients?

When we think about ER blockade versus SERDs, their [mechanisms of action are] slightly different, and as such, they may have differences in efficacy as well as toxicity. When we consider efficacy, if we have a modulator that induces degradation, that may overcome some genomic alteration or mutation that overcomes just the simple blockade; there is potential. However, how we manipulate the ER also possesses the potential to impact toxicity profiles.

What are some of the adverse events (AEs) linked with AIs?

AIs are widely used in the management of breast cancer in all phases. These are incredibly important drugs that have enhanced our ability to treat this disease, but they’re not without AEs. For example, a significant number of patients have arthralgia or joint discomfort. We also know that these agents are linked with accelerated bone loss because estrogen helps maintain bone integrity over time; that can relate to future risk for skeletal-related events independent of breast cancer. Many other AEs remain important to a reasonable percentage of patients, including menopausal symptoms like hot flashes, but also vaginal dryness or vulvovaginal atrophy, all of which can significantly impact quality of life.

Do you recommend testing for this type of mutation throughout a patient’s disease course?

The timing of [the development of] ESR1 [mutations] is increasingly coming into focus. We know that it’s very rare at the time of diagnosis; it’s possible that it’s present in a small subclone that’s not detectable in a single biopsy. After first-line therapy, the [likelihood of the development of this mutation] increases, and we know that the proportion of patients [with this mutation] increases over time. While a patient may not have developed an ESR1 mutation after 1 line of antiestrogen therapy, they may subsequently develop it.

One challenge in [terms of testing] is, we know from a patient perspective and from patient advocates that biopsies are sometimes difficult, painful, or risky. While it’s important to obtain biopsies to ensure that we know what the receptor subtype is, if we’re specifically looking for 1 mutation or a mutation in the ESR1 gene, another alternative is to consider a liquid biopsy, or ctDNA.

How often are liquid biopsies being used in the breast cancer space?

The potential for the use of liquid biopsy continues to grow, but there are pros and cons [to their use]. Tissue biopsies still have some benefits. In many ways, we are finding that [these approaches] may be complementary over time. For example, if you need multiple samples, a liquid biopsy might be a good fit. Whereas, if you need to look at the receptors, tissue biopsy is still the gold standard.

After progression, are patients with ER-positive, HER2-negative breast cancer less likely to respond to subsequent therapy?

For patients with metastatic ER-positive, HER2-negative breast cancer, we have an increasing number of treatment options. The standard first-line option is an AI with a CDK4/6 inhibitor. However, for patients with ESR1 mutations, it’s not clear whether they fit exactly into the standard paradigm. In the PALOMA-3 trial, palbociclib (Ibrance) plus fulvestrant was superior to fulvestrant alone for ESR1-mutation carriers. However, the exact sequencing and what therapy is optimal after AIs and CDK4/6 inhibitors remains unclear.

What are some of the studies addressing this patient subgroup?

First-line therapy for patients with ER-positive, HER2-negative metastatic breast cancer has increasingly come into focus. AIs plus CDK4/6 inhibitors have shown significant progressionfree survival benefit and now an overall survival benefit. Beyond first-line therapy though, many questions remain. Should subsequent therapy focus on SERDs? Is there utility in continuing CDK4/6 inhibitors? Trials such as the PACE trial [examined that question]. Will an alternative approach, such as targeting the ER itself, like the ELAINE trial with lasofoxifene, [be beneficial]? Should we focus on other pathways, such as the PI3K/AKT/mTOR pathway, with either PI3K inhibitors such as alpelisib (Piqray) or mTOR inhibitors such as everolimus (Afinitor)?

Could you discuss the design of the ELAINE trial with lasofoxifene?

The ELAINE trial is a phase II study randomizing patients to receive either lasofoxifene, a daily oral pill, versus fulvestrant at standard dosing. Patients are eligible for enrollment if they received an AI plus a CDK4/6 inhibitor in the first-line setting and had 0 or 1 line of prior chemotherapy. We’re evaluating whether lasofoxifene may have specific activity in patients with ESR1 mutations, so only those with a detected ESR1 mutations are eligible for the study.

What is the mechanism of action for lasofoxifene? What sets it apart from other agents?

Lasofoxifene is a very interesting agent; it was originally developed as a selective ER modulator and has undergone extensive safety testing previously looking at vulvovaginal atrophy and bone health, such as the PEARL study, which had enrolled over 8600 patients. The agent is very well tolerated.

Some more recent work has suggested that [lasofoxifene] has specific activity against ESR1-mutated breast cancers. While these cancers appear to have a more aggressive phenotype and may be resistant to many standard antiestrogen approaches, lasofoxifene was effective in reducing tumor size in mouse models. Because it has excellent safety data, I believe that if lasofoxifene is shown to be effective, it [could be a promising option] for this difficult-to-treat subgroup.

The agent received a fast track designation from the FDA. If eventually approved, what would the clinical implications be?

Lasofoxifene recently received FDA fast track status due to its extensive preexisting safety data. Relative to other individual agents or combinations that may have more challenging toxicity profiles, having an antiestrogen approach for ESR1-mutated breast cancers that’s well-tolerated would really be a breath of fresh air. Where such an agent fits within the landscape of other therapies and what sequencing will look like remains to be seen.

Where will future research focus in ESR1-mutant breast cancers?

Really intense research efforts are being made in terms of ESR1-mutation carriers. One group is examining specific ESR1 mutations, how [those mutations] change breast cancer at the cellular level in terms of its transcriptional profile, epigenomic changes, and how ESR1 interacts with other pathways. I believe that all of this work is expanding our understanding of this specific resistance mutation, which is increasingly important. We see that the proportion of patients with ER-positive, HER2-negative metastatic breast cancer who develop this [mutation] ranges from 20% to 30% or maybe even higher. [ESR1] an incredibly common resistance mutation as we have a huge number of patients with this disease. Therefore, developing optimal and new ways to target this particular set of mutations is going to be critical as we continue to move the field forward.

References

  1. Plourde PV, Schwartzberg LS, Greene GL, et al. An open-label, randomized, multi-center phase 2 study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic ER+/HER2 positive breast cancer (MBC) with an ESR1 mutation. Cancer Res. 2019;79(suppl 4, abstr OT1-01-02). doi: 10.1158/1538-7445.SABCS18- OT1-01-02.
  2. Sermonix receives FDA fast track designation for investigational drug lasofoxifene [news release]. Columbus, OH: Sermonix Pharmaceuticals LLC; May 28, 2019. bit.ly/2HH9Ofm?rel=0. Accessed November 13, 2019.