Diagnostic Advances Distinguish Actionable Drivers of Early Progression in ER+ Breast Cancer

Ahmed Elkhanany, MD

Understanding individual mechanisms of resistance and identifying driver mutations can help determine subsequent targeted treatment options for patients who experience early progression while receiving first-line therapy for estrogen receptor (ER)–positive metastatic breast cancer, according to Ahmed Elkhanany, MD.

“These patients will benefit from [us] taking the time to understand their biology and trying to tailor the next line [of therapy] for them,” Elkhanany said. “Otherwise, unfortunately, standard-of-care [SOC] regimens might not be the most suitable options.”

In May 2023, the National Comprehensive Cancer Network (NCCN) updated their guidelines to recommend ¹⁸F-Fluorestradiol (FES) FES positron emission tomography (PET) screening under certain circumstances during systemic staging for patients with recurrent or metastatic ER-positive breast cancer.¹ This update to the NCCN guidelines follows the October 2022 publication of recommendations by the Society of Nuclear Medicine and Molecular Imaging (SNMMI) regarding the appropriate use of ER-targeted PET imaging. SNMMI recommends the use of FES PET to assess ER status in nondiagnostic lesions, as well as in lesions that are difficult to biopsy, and notes that FES PET may also be an appropriate biopsy alternative in some lesions.² Additionally, the recommendations state that this approach is appropriate when selecting second-line endocrine therapy after metastatic disease progression.²

In an interview with OncLive^®, Elkhanany discussed unmet needs in patients with ER-positive breast cancer who progress on frontline therapy, treatment considerations for these patients, and how FES PET imaging may benefit this population.

Elkhanany is an assistant professor of medicine in the Division of Hematology & Oncology at The University of Alabama at Birmingham School of Medicine, as well as an associate scientist at the O’Neal Comprehensive Cancer Center and an associate scientist at the Center for Clinical and Translational Science at The University of Alabama at Birmingham.

OncLive: What is the typical disease course and prognosis of patients with standard-risk ER-positive metastatic breast cancer, and how does this compare with the disease course and outcomes in patients who experience early progression?

Elkhanany: Patients with hormone receptor–positive metastatic breast cancer typically do much better than patients with other subtypes of breast cancer, with an average median overall survival of approximately 3 to 5 years. There are varieties. [Patients with] bone-only disease, for example, tend to do significantly better than [those with] visceral disease.

Most of the patients we see in the first-line setting have closer to 2 years of progression-free survival on the first line alone. Early progression [occurs in] a heterogeneous population. Broadly, you can think of these patients in 2 large groups. On one hand, you have the group who were diagnosed with de novo metastatic ER-positive disease and progressed within the first 6 months on their treatment. On the other hand, you have the patients who have been diagnosed with early-stage breast cancer, are in the process of receiving or maybe just finished their adjuvant endocrine therapy, and develop metastatic disease while on aromatase inhibitors [Ais], hormone therapy, or shortly after finishing their planned course. These are typically the patients who we consider [to have progressed early]. These patients tend to do slightly worse than those who respond to first-line therapy. There is usually some underlying biological heterogeneity that drives these early progressions.

What are some clinical indicators of ER-positive early progression?

Most of these patients have bone-only disease or wound-dominant disease with their metastases in the bone. A few might have foci in the liver or lung. Few have brain-specific foci. With all these patients in the metastatic setting, we’re anticipating disease control for approximately 3 years with the first line. However, we discuss signs of early progression [with patients]. This becomes particularly important for the cohort that has progressed while on adjuvant therapy.

Some signs of progression include worsening or new bone disease, which might manifest with bone pain or occasionally fractures, and any pain or change in their mental status. In general, [these signs are] tailored toward the patient’s condition. To try to be more proactive, we routinely do staging scans [at around] 8 weeks or 12 weeks. Some of these patients might be on clinical trials, which have their own [scan] schedules. Almost always, we start with frequent and persistent staging imaging. As we learn more about the clinical course of the disease, we might relax the intervals between imaging.

How do you approach treatment for patients who require earlier intervention with second-line therapies, and what may be the role for genomic sequencing in this setting?

Patients who have progressed within the first 6 months [of frontline therapy] are different, both biologically and in the course of their treatment. In the current literature, most of the recommendations for the first line are a combination of a CDK4/6 inhibitor and an adjuvant hormone therapy, whether that be an AI or a selective estrogen receptor modulator [SERM]. This might be slightly different for patients who progressed after adjuvant therapy. This is complicated and gets muddied with new data on adjuvant CDK4/6 inhibitors.

That population aside, when I see patients who had disease progression shortly after starting their first line, my first question is: What’s the biological driver of this early progression? Some known drivers include ESR1 mutations, PIK3CA mutations, and CCND1 amplifications, which can cause resistance to CDK4/6 inhibitors. Other drivers are not as actionable, including TP53, which, though rarely seen in ER-positive disease, can happen, and can drive the disease further. [Some] drivers are not as common but are also actionable, for example, NTRK fusions. Those have specific FDA approvals.

Because of this heterogeneity, genomic testing is essential in these patients to understand if there are actionable mutations driving this primary resistance, and if so, to target those mutations specifically. We typically use either a tissue-based or liquid biopsy. Sometimes we do both to get a clearer comprehensive view of the genomic profile. Liquid biopsy is great for getting a gestalt view of all the actionable mutations across different metastatic foci, however, it also might not catch certain mutations that have a low allele ratio. In patients like that, I would try to do due justice with both liquid-based and tissue-based biopsy.

Alongside these, it’s important to also understand the behavior of the disease. From an imaging standpoint: Where is the progression happening? Is it still bone-only progression, or [is there] progression into the viscera? [Patients with] visceral involvement that early are at a slightly higher risk.

Thirdly, I would look again into the receptor status for these patients. Receptor status is known to change and become discordant between primary and metastatic disease and within the metastatic spectrum itself. It’s not uncommon that we close off 1 receptor using an anti-HER2 or anti–estrogen-based therapy and then upregulate ER negativity. Confirming that the diagnosis remains ER positive, confirming the metastatic foci, understanding their location, and getting a better picture of the genomic profile of this disease [are important]. We typically want to gather this information within a short timeframe, between 3 to 5 weeks, so we have a solid plan for the second line.

How might health care professionals adapt their practices given the updates to the NCCN imaging guidelines?

There have been many changes in the way we [use] targeted imaging over the past few months. That started with the slow but important introduction of FES PET. The NCCN guidelines recommend the use of FES PET for ER-positive disease in certain circumstances. Some of these circumstances include a situation where you cannot do a biopsy. Early progression is probably 1 of these indications because you want to evaluate the extent of disease from the imaging standpoint, but also you want to confirm the biology of the disease, its ER status. That’s where FES PET works best, because it gives both a spatial and functional mapping of cancer, so you get where it is and the amount of [estrogen it has].

Fluorodeoxyglucose [FDG] PET uses the Warburg effect. It uses metabolic uptake within the cells and depends on cellular activity. However, FES PET does not depend on the metabolic activity, but rather, on estrogen uptake, which is a functional property of the cell. Cancerous foci that are faint with even a normal uptake on FDG PET, because they’re not metabolizing much sugar, [may have a] clear uptake on FES PET because it stains [based on] estrogen activity.

If FES PET is available, [in early progression, it can] give us a bird’s eye view on where the cancer is and a functional estimate about its activity. It’s still rare to find facilities that have FES uptake, [although] more and more facilities are contributing to it. FDG PET, computed tomography [CT] scans, and bone scans are alternatives. However, if a patient has access to a facility that offers FES PET, I favor that over regular PET CT. With these patients, we want to be 1 step ahead of cancer by doing more sensitive tests.

This poses a few challenges. What if a few foci light up on FES PET that did not light up on FDG PET, for example? [What about] asymptomatic foci that the patient didn’t know about? It’s early to see how approaching these different metastatic sites would be helpful, or whether we should make a treatment decision based on a single FES PET uptake. However, we would still treat [these patients] in the same way we would treat [those with an] FDG PET uptake. If there’s a symptomatic area, we might continue monitoring without bridging therapy.

Another logistical challenge is: What happens after the first FES PET? Do we repeat FES PET, or can we use FDG PET? This is a tough question because these are not the same. It’s essential to try to use 1 modality and continue with that modality, except maybe [for providers in an] area of expertise who can compare across modalities. That being said, in patients for whom you want to have an unequivocal idea about their disease behavior, sticking to 1 modality, at least in the early disease course, would probably be more beneficial.

This is still a new technology. It’s important to approach new technologies with caution. However, I’ve had many patients who underwent [FES PET] and its interpretation can be tricky. Interpreting FES PET should be a mutual effort between radiologists and oncologists because this scan synthesizes radiological expertise and estrogen uptake. There are situations where you see estrogen uptake in places you wouldn’t expect estrogen to be. This is the kind of discussion between radiology and oncology that we used to do but is now scarcer because everybody is busy. These functional images should bring back the discussion. Reading FES PET should involve both parties.

What ongoing research may help clarify outstanding uncertainties in this setting?

There are always clinical trials targeting patients with either rapid progression or specific, actionable, targetable mutations. [The phase 2] NCI-MATCH [NCT02465060] and TAPUR [NCT02693535] trials are 2 basket trials looking for patients with a broad range of genomic alterations that match patients based on their genomic profile to 1 of their therapeutic lines. If a patient has been on a CDK4/6 inhibitor for a couple of months and then has unequivocal progression, I would think of a clinical trial. With this group of medicines, I expect to see 2 to 3 years of disease control, so when patients come in within 6 months, that tells me we’re dealing with a disease that has a different biology than our SOC [can manage]. Genomic medicine and precision oncology trials are 1 [avenue].

Also, several trials [enroll] patients with ESR1 mutations, which is likely 1 of the driving factors behind their progression. In that [setting], we have the FDA approval of elacestrant [Orserdu], a novel selective estrogen receptor degrader [SERD] that works for patients with ESR1 mutations. Prior to that approval, we used fulvestrant [Faslodex], a SERD, for these patients, although it was [indicated through] a pan approval that was not necessarily for [patients with] ESR1 mutations. Several trials are ongoing for ESR1-specific mutations in combination with other agents. There are also [trials with] SERMs, [such as] lasofoxifene [Fablyn], that are trying to address these patients. [These trials] don’t specifically look for early progressions, however, the patients [enrolled] typically have a higher percentage of ESR1 mutations.

PIK3CA is another mutation, and clinical trials are aiming to add to the current PIK3CA [inhibitors]. Trials are also looking to combine different modalities of mTOR pathway inhibition on top of ESR1-targeted agents [for patients] who have both [ESR1 and PIK3CA] mutations, which is not uncommon. When patients progress quickly early in their disease, it is a good idea to consider available clinical trials.

What is your main message for medical oncologists and radiologists?

We see early progression in the real world a lot. As of a few years ago, we didn’t have any major tools to address these patients’ needs properly because we had no actionable targets. But now we have 2, almost 3, actionable targets, along with several pan-cancer targets like PD-L1 and NTRK mutations.

References

1. GE HealthCare announces FES PET imaging recommendation in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®). News release. GE HealthCare. May 24, 2023. Accessed June 15, 2023. https://www.gehealthcare.com/about/newsroom/press-releases/ge-healthcare-announces-fes-pet-imaging-recommendation-in-nccn-clinical-practice-guidelines-in-oncology-nccn-guidelines
2. Ulaner GA, Mankoff DA, Clark AS, et al. Appropriate Use Criteria for estrogen receptor-targeted PET imaging with 16α¹⁸F-Fluoro-17β-Fluoroestradiol. October 2022. Accessed June 15, 2023. https://s3.amazonaws.com/rdcms-snmmi/files/