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Molecular Profiling, Endocrine Sensitivity Are Key to Managing Later-Line HR+/HER2-Negative Breast Cancer

Supplements and Featured Publications, Molecular Testing and Evolving Treatment Strategies in HR+/HER2– Advanced Breast Cancer, Volume 1, Issue 1

Erika P. Hamilton, MD, discusses the current role of CDK4/6 inhibitors and evolving targeted therapies in advanced HR-positive, HER2-negative breast cancer.

Erika P. Hamilton, MD

Erika P. Hamilton, MD

Although the combination of an aromatase inhibitor (AI) and a CDK4/6 inhibitor remains the standard of care for frontline management of advanced hormone receptor (HR)–positive, HER2-negative breast cancer, an increasing reliance on molecular profiling and the lack of predictive tools to reliably stratify patients by endocrine sensitivity continue to complicate treatment selection and sequencing in the second line and beyond, particularly as more agents become available in later settings, according to Erika P. Hamilton, MD.

“It's exciting to have all these new agents. It’s certainly good for patients, but it also makes things a little bit more complicated.” Hamilton said in an interview with OncLive®. “One of the big unmet medical needs [is] being able to have a good assay that can tell us whether our patient is still endocrine-sensitive.”

In the interview, Hamilton discussed the current first-line arsenal in HR-positive breast cancer and addressed the complexity of second-line treatment after progression on a frontline CDK4/6 inhibitor–based regimen. She also emphasized the growing role of molecular testing and expressed anticipation for upcoming data with the oral selective estrogen receptor degrader (SERD) camizestrant (AZD9833), which may shift practice patterns around testing for ESR1 mutations in patients still receiving first-line therapies.

Hamilton is the director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee.

OncLive: What are the current challenges in the frontline management of advanced HR-positive breast cancer?

Hamilton: Things are becoming a little clearer [regarding frontline treatment selection]. We definitely have a standard of care in the first-line setting, which is an AI combined with a CDK4/6 inhibitor. We have 3 choices of CDK4/6 inhibitors, and it's standard to use [a CDK4/6 inhibitor–based] combination in the first line. The one small caveat [applies to] patients whose disease progressed within 12 months of an AI in the adjuvant setting, where we use fulvestrant [Faslodex]. Specifically, for those patients whose disease progressed within 12 months in the adjuvant setting and have a PI3K mutation, that's where alpelisib [Piqray] becomes a possibility, which is a [shift] from our standard approach. However, the majority of patients receive an AI [in combination with] a CDK4/6 inhibitor.

Luckily, [CDK4/6 inhibitors] are generally well tolerated. We do see fatigue and neutropenia, but we've become very familiar with neutropenia and are comfortable recognizing that it doesn't translate into febrile neutropenia or illness for our patients. It's exciting to see that with these data, overall survival [OS] is now exceeding 5 years. As we get better agents in the second- and third-line settings and beyond, I anticipate that we will see OS lengthen even further.

What are some factors you consider when selecting a CDK 4/6 inhibitor?

The selection of CDK4/6 inhibitors is a big topic. Several years ago, we were probably almost all using palbociclib [Ibrance]. Despite the fact that progression-free survival [PFS] looks identical across these 3 compounds, with palbociclib [plus letrozole], we did not see a benefit in OS [vs placebo plus letrozole in the phase 3 PALOMA-2 trial (NCT01740427)].1

[Instead, we had] much stronger data for ribociclib [Kisqali], as well as abemaciclib [Verzenio], in that space. As a result, many [practitioners] have switched to ribociclib as their CDK4/6 inhibitor of choice in the first-line setting. However, this is not universal, and these agents have different adverse effect [AE] profiles. Palbociclib and ribociclib [are associated with] more severe neutropenia, [whereas] abemaciclib has more gastrointestinal toxicity, and ribociclib also has the caveat of needing to monitor EKGs because of potential QTc prolongation. For patients on a lot of cardiac medications or other medications that can prolong the QTc, ribociclib [may not be] a good choice.

We also need to monitor liver function tests with ribociclib. In general, ribociclib [should be] considered [first], but there are certainly patients with other comorbidities or medications [that influence the selection of] CDK4/6 inhibitors. In reality, all 3 are utilized in the first-line setting.

How do you approach treatment selection after progression on a frontline CDK4/6 inhibitor–based regimen? When would you consider switching to another CDK4/6 inhibitor in that setting?

[The management of] second-line, estrogen receptor [ER]–positive breast cancer has become infinitely more complicated. This is where our mutational profiling is extremely actionable. We have elacestrant [Orserdu] for patients with an ESR1 mutation. We have alpelisib for patients with a PI3K mutation, and for patients displaying a PI3K, AKT, or PTEN mutation, we have capivasertib [(Truqap) plus fulvestrant]. [There are] a variety of very actionable mutations, and it's very clear that single-agent fulvestrant is just not good enough in a post–CDK4/6 inhibitor world. We have multiple randomized trials showing us that PFS with fulvestrant alone post–CDK4/6 inhibition is less than 2 months, which is clearly not good enough for our patients. We [should be thinking] about either using fulvestrant [in combination] with one of those targeted agents, or perhaps elacestrant [alone].

The other data we’ve gotten more recently for a ‘bland’ mutation profile, where we don’t see one of those PI3K, AKT, PTEN, or ESR1 mutations, is reusing CDK4/6 inhibitors. Specifically, the phase 3 postMONARCH study [NCT05169567] probably [provides] our strongest dataset in this setting [and supports] switching the CDK4/6 inhibitor to abemaciclib, particularly if the patient first received ribociclib or palbociclib. This does [generate] a longer PFS. [Thus,] for the most part, we’re thinking about using combinations in that second-line setting, as long as our patient [experienced] benefit from a CDK4/6 inhibitor in the first line.

When and how often are you conducting molecular testing? More specifically, when are you looking for an ESR1 mutation?

I'm testing after [progression on] their first-line CDK4/6 inhibitor, [because] that's really where it's actionable. [ESR1 mutations are] not as actionable in the first line because they are exceedingly rare [in that setting], so I'm testing there [after patients receive a CDK4/6 inhibitor].

[ESR1 is also] a bit less actionable in the later lines. The majority of those patients have [developed] endocrine resistance at that point. We're not necessarily going back to endocrine therapy, but sometimes we can. Honestly, this has become a challenging area because ESR1 mutations are helpful. They're certainly linked to therapeutic benefit and can give us a hint as to whether patients might be a bit more likely to still have endocrine-sensitive tumors.

However, it's not perfect. If we look at the data from the [phase 3] EMERALD trial [NCT03778931], approximately 40% of patients were progressing at their first scan, regardless of which drug they received. Endocrine resistance is a real problem in the post–CDK4/6 inhibitor landscape, and we don't have a great way [to determine] who will get continued benefit from endocrine therapy. That's an unmet clinical need right now.

How might data from the phase 3 SERENA-6 trial (NCT04964934) inform the role of camizestrant in advanced HR-positive breast cancer?

The implications for camizestrant are pretty broad. Recall that we've already seen results from a randomized—although not registrational—trial evaluating fulvestrant vs camizestrant at 2 different doses: 75 mg and 150 mg. That study was positive, [showing that] camizestrant at either dosing schedule [demonstrated superior efficacy vs] fulvestrant. Those trials are ongoing in the metastatic setting, and there are ongoing first-line trials [of camizestrant] in combination with CDK4/6 inhibitors.

The first [phase 3 trial] we're going to see [data read out from] is SERENA-6. SERENA-6 asks an interesting question—one that we haven’t talked a whole lot about in breast oncology before—[about] what I would call the 1.5 line. These are patients who are on first-line therapy with an AI and CDK4/6 inhibitor, and then have the emergence of an ESR1 mutation in the absence of disease progression. [Altering therapy] is not really second-line therapy because patients haven’t progressed, but they have an ESR1 mutation. [This] tells us something is changing and they’re likely to progress soon. The trial looked at either continuing the AI and CDK4/6 inhibitor [regimen] or switching to camizestrant [plus] a CDK4/6 inhibitor. [According to a] press release, [the study] was positive for [a PFS improvement when switching to the camizestrant regimen].2

There are a couple of implications here. First, this will be the first registrational trial of camizestrant, which is important, even though we know this is a great drug. The other is that it could potentially change our practice pattern around testing for mutations. Minimal residual disease [MRD] has been discussed a lot, but we don’t have any good data for that in breast cancer. Testing for MRD is possible, and it can determine whether somebody is likely to have a poor prognosis; however, we don’t have any information on the back end that anything we do helps that patient. There isn’t utility in testing for MRD, but this could [support testing] for something like an ESR1 mutation as patients are on first-line therapy. I’m very excited for everyone to see [the full] results [from SERENA-6].

As more novel agents, such as antibody-drug conjugates (ADCs) and oral SERDs, emerge in HR-positive breast cancer, how can assays help determine the appropriate treatment sequence for patients?

It's exciting to have all these new agents. It’s certainly good for patients, but it also makes things a little bit more complicated. We also have to be careful when we talk about combinations of drugs. When we add drugs together, tolerability goes down. Inevitably, there are more AEs when [a patient is] taking multiple medications, so we have to keep that in mind.

From a patient-tolerance perspective, I've touched on one of the big unmet medical needs—being able to have a good assay that can tell us whether our patient is still endocrine-sensitive and signaling through that endocrine axis.

We've certainly seen great data with the ADCs. When we think about moving to chemotherapy for a patient with HR-positive disease, we [should be considering] ADCs now. However, we don’t want to move to ADCs before we've exhausted our endocrine therapy. [An assay could] help us determine who should continue to get further lines of endocrine therapy and who is ready to move to ADCs. Then, some of the novel endocrine backbones, whether we're talking about camizestrant or vepdegestrant [ARV-471], as well as some of the other oral SERDs or complete estrogen receptor antagonists are [coming down] the pipeline.

References

  1. Slamon DJ, Diéras V, Rugo HS, et al. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. J Clin Oncol. 2024;42(9):994-1000. doi:10.1200/JCO.23.00137
  2. Camizestrant demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival in 1st-line advanced HR-positive breast cancer with an emergent ESR1 tumour mutation in SERENA-6 phase III trial. News release. AstraZeneca. February 26, 2025. Accessed April 16, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/camizestrant-improved-pfs-in-1l-hr-breast-cancer.html

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